PROJECT DESCRIPTION The MYC family of oncogenes plays a key role in driving the growth of a large number of human cancers. Neuroblastoma is a prototypical MYC-driven cancer, with MYCN amplified neuroblastoma representing a particularly aggressive form of this disease. Neuroblastoma therefore provides an ideal setting in which to test novel agents that target MYC family genes. SF1126 is an investigational integrin-targeted inhibitor of PI3- kinase and BRD4 that shows preclinical activity in models of MYCN amplified neuroblastoma. SF1126 has completed phase 1 testing in adults with a range of cancers, with a favorable toxicity profile. The FDA has granted an IND for the conduct of an investigator-initiated phase 1 study of SF1126 in children with relapsed or refractory neuroblastoma. This phase 1 study is being conducted by the New Approaches to Neuroblastoma Therapy (NANT) consortium, a group of leading children?s hospitals in the United States and Canada with expertise in the care of children with advanced neuroblastoma. The study consists of two parts: a dose escalation part and a dose expansion part focused on patients with MYC or MYCN-driven neuroblastoma. In the dose escalation part, a range of SF1126 doses is being evaluated using a standard 3+3 design to define a recommended phase 2 pediatric dose. This part of the study will include patients with relapsed or refractory neuroblastoma regardless of molecular subtype. In the dose expansion part, patients with MYCN amplified neuroblastoma or Myc-expressing neuroblastoma will be treated at the recommended phase 2 pediatric dose to assess the activity of SF1126 in this molecularly defined subgroup. Key secondary objectives will include evaluation of the pharmacokinetic profile of SF1126 in this pediatric population, assessment of pharmacodynamic markers of SF1126 activity, and evaluation of surrogate markers of antitumor activity. This award will support completion of this trial by: 1) enabling manufacture and vialing of additional SF1126; 2) funding the research team conducting the trial; 3) supporting effort at NANT institutions who enroll patients; and 4) funding central review of response. Successful completion of the trial will provide proof-of-concept for the role of SF1126 in targeting MYC-driven cancers. Our results will enable further development of this agent in neuroblastoma and other MYC-driven tumors.